SCN5A Variant G274C Detail

We estimate the penetrance of LQTS for SCN5A G274C around 18% and the Brugada syndrome penetrance around 19%. SCN5A G274C was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. G274C is present in 1 alleles in gnomAD. G274C has been functionally characterized in 0 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Mild_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (2 diagnosed with Brugada syndrome) and 5 individuals for LQTS (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A G274C around 18% (1/11) and the Brugada syndrome penetrance around 19% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-8.78 1 0.56 0.977 22 16
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance Density is our previously published method to calculate the average BrS/LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT3 BrS1 Other Other Disease
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 12 1 2 - -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

G274C has 63 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
328 13
364 14
277 4
271 10 L271V,
266 14 L266H,
326 13
276 5 L276P, L276Q,
348 11 P348A,
270 10 Q270K,
360 13
279 10
385 10 A385T,
1552 13 Q1552L, Q1552R,
355 8 F355I, F355C,
1549 10
278 6 H278R, H278D,
356 7 D356N,
361 12
343 6
327 12
384 9 S384T,
354 7
329 14
386 13 G386E, G386R,
349 15 D349N,
267 14
1550 6
357 11
272 7
341 11 C341Y,
274 0 G274C,
273 5
325 11 L325R,
392 15
324 15
389 13 Y389H, Y389X,
269 9
1620 14 T1620K, T1620M,
345 10
275 4 N275K,
383 14
280 14 C280Y,
323 14
347 9
382 14
1548 12 E1548K, G1548K,
351 12 G351D, G351V, G351C, G351S,
265 14 A265V,
1619 15 P1619Q, P1619L, c.4856delC,
358 14
342 11
1551 9 D1551Y, D1551N,
346 11 E346G, E346D, E346X, E346K,
359 14 A359T, p.A359PfsX12,
344 9 A344S,
381 10 c.1141-3C>A, c.1140+1G>A,
352 14 Y352C,
380 12
268 10 G268S,
377 13
281 15 V281M,
353 10 T353I,
1623 14 c.4867delC, R1623X, R1623Q, R1623L,